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1. Identifying and treating resistant hypertension in PRECISION: A randomized long‐term clinical trial with aprocitentan

Author

Parisa Danaietash, Pierre Verweij, Ji‐Guang Wang, George Dresser, Ilkka Kantola, Mary Katherine Lawrence, Krzysztof Narkiewicz, Markus Schlaich, Marc Bellet, and the PRECISION investigators

Subjects
aprocitentan, blood pressure, endothelin receptor antagonist, pseudoresistant hypertension, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel‐group Phase 3 study and its three‐part design assesses the short‐term and sustained long‐term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single‐tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single‐blind placebo run‐in period. The 4‐week placebo run‐in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4‐week double‐blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32‐week single‐blind part with aprocitentan 25 mg; and (3) a 12‐week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Published
2022
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2. Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies

Author

Paul Ratner, Charles P. Andrews, Frank C. Hampel, Bruce Martin, Dale E. Mohar, Denis Bourrelly, Parisa Danaietash, Sara Mangialaio, Jasper Dingemanse, Abdel Hmissi, and Jay van Bavel

Subjects
Allergy, Rhinitis, Efficacy, Safety, Mountain Cedar pollen, Setipiprant, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks. Methods A Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100–1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS). Results 579 participants were randomized in the Phase 2 trial (mean age 41.6–43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5–40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (−0.15 [95% CI −0.29, −0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (−0.02 [95% CI −0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile. Conclusions The Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies. Trial registration NCT01241214 and NCT01484119

Published
2017
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3. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Author

Schlaich, M.P., Bellet, M., Weber, Manuel, Danaietash, P., Bakris, G.L., Flack, J.M., Dreier, R.F., Sassi-Sayadi, M., Haskell, L.P., Deinum, J., Narkiewicz, K., Wang, J.G., Schlaich, M.P., Bellet, M., Weber, Manuel, Danaietash, P., Bakris, G.L., Flack, J.M., Dreier, R.F., Sassi-Sayadi, M., Haskell, L.P., Deinum, J., Narkiewicz, K., and Wang, J.G.

Abstract

Item does not contain fulltext, BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square m

Published
2022

4. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Author

Schlaich, M, Bellet, M, Weber, M, Danaietash, P, Bakris, G, Flack, J, Dreier, R, Sassi-Sayadi, M, Haskell, L, Narkiewicz, K, Wang, J, Reid, C, Katz, I, Ajani, A, Biswas, S, Esler, M, Elder, G, Roger, S, Colquhoun, D, Mooney, J, De Backer, T, Persu, A, Chaumont, M, Krzesinski, J, Vanabsche, T, Girard, G, Pliamm, L, Schiffrin, E, Merali, F, Dresser, G, Vallee, M, Jolly, S, Chow, S, Mu, J, Yu, J, Yuan, H, Feng, Y, Zhang, X, Xie, J, Lin, L, Soucek, M, Widimsky, J, Cifkova, R, Vaclavik, J, Ullrych, M, Lukac, M, Rychlik, I, Guldager Lauridsen, T, Kantola, I, Taurio, J, Ukkola, O, Ormezzano, O, Gosse, P, Azizi, M, Courand, P, Delsart, P, Tartiere, J, Mahfoud, F, Schmieder, R, Stegbauer, J, Lurz, P, Koziolek, M, Ott, C, Toursarkissian, N, Tsioufis, K, Kyfnidis, K, Manolis, A, Patsilinakos, S, Zebekakis, P, Karavidas, A, Denes, P, Bezzegh, K, Zsom, M, Kovacs, L, Sharabi, Y, Elias, M, Sukholutsky, I, Yosefy, C, Kenis, I, Atar, S, Volpe, M, Lorenza, M, Taddei, S, Grassi, G, Veglio, F, Son, J, Kim, J, Park, J, Lee, C, Lee, H, Raugaliene, R, Marcinkeviciene, J, Kavaliauskiene, R, Deinum, J, Kroon, A, van den Born, B, Januszewicz, A, Tykarski, A, Walczewska, J, Gaciong, Z, Wiecek, A, Chrostowska, M, Kleinrok, A, Krekora, J, Kania, G, Podrazka-Szczepaniak, A, Golawski, C, Podziewski, M, Kaczmarek, B, Skoczylas, G, Wilkolaski, A, Wozniak, I, Janik-Palazzolo, M, Rewerska, B, Konradi, A, Shvarts, Y, Pecherina, T, Nikolaev, K, Liudmila, G, Orlikova, O, Mordovin, V, Petrochenkova, N, Kamalov, G, Kosmacheva, E, Tyrenko, V, Gorbunov, V, Obrezan, A, Supryadkina, T, Ler, I, Kotenko, O, Kuzin, A, Martinez, F, Redon, J, Oliveras, A, Beltran Romero, L, Shatylo, V, Rudenko, L, Bazylevych, A, Rudyk, Y, Karpenko, O, Stanislavchuk, M, Tseluyko, V, Kushnir, M, Asanov, E, Sirenko, Y, Yagensky, A, Collier, D, Gupta, P, Webb, D, Macleod, M, Mclay, J, Peace, A, Arora, S, Buchanan, P, Harris, R, Degarmo, R, Guillen, M, Karns, A, Neutel, J, Paliwal, Y, Pettis, K, Toth, P, Wayne, J, Butcher, B, Diller, P, Oparil, S, Calhoun, D, Brautigam, D, Goldman, J, Rashidi, A, Aslam, N, Haley, W, Andrawis, N, Lang, B, Miller, R, Powell, J, Dewhurst, R, Pritchard, J, Khanna, D, Tang, D, Gabra, N, Jones, C, Scott, C, Luna, B, Mussaji, M, Bhagwat, R, Bauer, M, Mcginty, J, Nambiar, R, Sangrigoli, R, Ross Davis, W, Eaves, W, Mcgrew, F, Awad, A, Bolster, E, Scott, D, Kalirao, P, Dabel, P, Calhoun, W, Gouge, S, Warren, M, Lawrence, M, Jamal, A, El-Shahawy, M, Mercado, C, Kumar, J, Velasquez-Mieyer, P, Busch, R, Lewis, T, Rich, L, Schlaich, Markus P, Bellet, Marc, Weber, Michael A, Danaietash, Parisa, Bakris, George L, Flack, John M, Dreier, Roland F, Sassi-Sayadi, Mouna, Haskell, Lloyd P, Narkiewicz, Krzysztof, Wang, Ji-Guang, Reid, Christopher, Schlaich, Markus, Katz, Ivor, Ajani, Andrew, Biswas, Sinjini, Esler, Murray, Elder, Grahame, Roger, Simon, Colquhoun, David, Mooney, John, De Backer, Tine, Persu, Alexandre, Chaumont, Martin, Krzesinski, Jean-Marie, Vanabsche, Thomas, Girard, Ginette, Pliamm, Lew, Schiffrin, Ernesto, Merali, Fatima, Dresser, George, Vallee, Michel, Jolly, Shivinder, Chow, Stephen, Wang, Jiguang, Mu, Jianjun, Yu, Jing, Yuan, Hong, Feng, Yingqing, Zhang, Xin, Xie, Jianhong, Lin, Ling, Soucek, Miroslav, Widimsky, Jiri, Cifkova, Renata, Vaclavik, Jan, Ullrych, Martin, Lukac, Martin, Rychlik, Ivan, Guldager Lauridsen, Thomas, Kantola, Ilkka, Taurio, Jyrki, Ukkola, Olavi, Ormezzano, Olivier, Gosse, Philippe, Azizi, Michel, Courand, Pierre-Yves, Delsart, Pascal, Tartiere, Jean Michel, Mahfoud, Felix, Schmieder, Roland, Stegbauer, Johannes, Lurz, Philipp, Koziolek, Michael, Ott, Christian, Toursarkissian, Nicole, Tsioufis, Konstantinos, Kyfnidis, Konstantinos, Manolis, Athanasios, Patsilinakos, Sotirios, Zebekakis, Pantelis, Karavidas, Apostolos, Denes, Pall, Bezzegh, Katalin, Zsom, Marianna, Kovacs, Laszlo, Sharabi, Yehonatan, Elias, Mazen, Sukholutsky, Ivetta, Yosefy, Chaim, Kenis, Irina, Atar, Shaul, Volpe, Massimo, Lorenza, Muiesan Maria, Taddei, Stefano, Grassi, Guido, Veglio, Franco, Son, Jung Woo, Kim, Jang-Young, Park, Joong-Il, Lee, Chang Hoon, Lee, Hae-Young, Raugaliene, Rasa, Marcinkeviciene, Jolanta Elena, Kavaliauskiene, Roma, Deinum, Jaap, Kroon, Abraham, van den Born, Bert-Jan, Januszewicz, Andrzej, Tykarski, Andrzej, Walczewska, Jolanta, Gaciong, Zbigniew, Wiecek, Andrzej, Chrostowska, Marzena, Kleinrok, Andrzej, Krekora, Jan, Kania, Grzegorz, Podrazka-Szczepaniak, Anna, Golawski, Cezary, Podziewski, Maciej, Kaczmarek, Barbara, Skoczylas, Grzegorz, Wilkolaski, Andrzej, Wozniak, Iwona, Janik-Palazzolo, Marzena, Rewerska, Barbara, Konradi, Alexandra, Shvarts, Yuriy, Pecherina, Tamara, Nikolaev, Konstantin, Liudmila, Gapon, Orlikova, Olga, Mordovin, Viktor, Petrochenkova, Natalia, Kamalov, Gadel, Kosmacheva, Elena, Tyrenko, Vadim, Gorbunov, Vladimir, Obrezan, Andrey, Supryadkina, Tatiana, Ler, Irina, Kotenko, Oleg, Kuzin, Anatoly, Martinez, Fernando, Redon, Josep, Oliveras, Anna, Beltran Romero, Luis, Shatylo, Valerii, Rudenko, Leonid, Bazylevych, Andriiy, Rudyk, Yurii, Karpenko, Oleksandr, Stanislavchuk, Mykola, Tseluyko, Vira, Kushnir, Mykola, Asanov, Ervin, Sirenko, Yuriy, Yagensky, Andriy, Collier, David, Gupta, Pankaj, Webb, David, MacLeod, Mary, McLay, James, Peace, Aaron, Arora, Samir, Buchanan, Patricia, Harris, Robert, Degarmo, Ronald, Guillen, Mario, Karns, Adam, Neutel, Joel, Paliwal, Yogesh, Pettis, Karlton, Toth, Phillip D., Wayne, Jeffrey M., Butcher, Bain, Diller, Phillip M., Oparil, Suzanne, Calhoun, David, Brautigam, Donald, Flack, John, Goldman, Jesse M., Rashidi, Arash, Aslam, Nabeel, Haley, William, Andrawis, Nabil, Lang, Brian, Miller, Randy, Powell, James, Dewhurst, Robert, Pritchard, James, Khanna, Dinesh, Tang, Dennis, Gabra, Nashwa, Park, Jean, Jones, Conigliaro, Scott, Cranford, Luna, Blanca, Mussaji, Murtaza, Bhagwat, Ravi, Bauer, Michael, McGinty, John, Nambiar, Rajesh, Sangrigoli, Renee, Ross Davis, William, Eaves, William, McGrew, Frank, Awad, Ahmed, Bolster, Eric, Scott, David, Kalirao, Paramjit, Dabel, Pascal, Calhoun, Wesley, Gouge, Steven, Warren, Mark, Lawrence, Mary Katherine, Jamal, Aamir, El-Shahawy, Mohamed, Mercado, Carlos, Kumar, Jayant, Velasquez-Mieyer, Pedro, Busch, Robert, Lewis, Todd, Rich, Lisa, Schlaich, M, Bellet, M, Weber, M, Danaietash, P, Bakris, G, Flack, J, Dreier, R, Sassi-Sayadi, M, Haskell, L, Narkiewicz, K, Wang, J, Reid, C, Katz, I, Ajani, A, Biswas, S, Esler, M, Elder, G, Roger, S, Colquhoun, D, Mooney, J, De Backer, T, Persu, A, Chaumont, M, Krzesinski, J, Vanabsche, T, Girard, G, Pliamm, L, Schiffrin, E, Merali, F, Dresser, G, Vallee, M, Jolly, S, Chow, S, Mu, J, Yu, J, Yuan, H, Feng, Y, Zhang, X, Xie, J, Lin, L, Soucek, M, Widimsky, J, Cifkova, R, Vaclavik, J, Ullrych, M, Lukac, M, Rychlik, I, Guldager Lauridsen, T, Kantola, I, Taurio, J, Ukkola, O, Ormezzano, O, Gosse, P, Azizi, M, Courand, P, Delsart, P, Tartiere, J, Mahfoud, F, Schmieder, R, Stegbauer, J, Lurz, P, Koziolek, M, Ott, C, Toursarkissian, N, Tsioufis, K, Kyfnidis, K, Manolis, A, Patsilinakos, S, Zebekakis, P, Karavidas, A, Denes, P, Bezzegh, K, Zsom, M, Kovacs, L, Sharabi, Y, Elias, M, Sukholutsky, I, Yosefy, C, Kenis, I, Atar, S, Volpe, M, Lorenza, M, Taddei, S, Grassi, G, Veglio, F, Son, J, Kim, J, Park, J, Lee, C, Lee, H, Raugaliene, R, Marcinkeviciene, J, Kavaliauskiene, R, Deinum, J, Kroon, A, van den Born, B, Januszewicz, A, Tykarski, A, Walczewska, J, Gaciong, Z, Wiecek, A, Chrostowska, M, Kleinrok, A, Krekora, J, Kania, G, Podrazka-Szczepaniak, A, Golawski, C, Podziewski, M, Kaczmarek, B, Skoczylas, G, Wilkolaski, A, Wozniak, I, Janik-Palazzolo, M, Rewerska, B, Konradi, A, Shvarts, Y, Pecherina, T, Nikolaev, K, Liudmila, G, Orlikova, O, Mordovin, V, Petrochenkova, N, Kamalov, G, Kosmacheva, E, Tyrenko, V, Gorbunov, V, Obrezan, A, Supryadkina, T, Ler, I, Kotenko, O, Kuzin, A, Martinez, F, Redon, J, Oliveras, A, Beltran Romero, L, Shatylo, V, Rudenko, L, Bazylevych, A, Rudyk, Y, Karpenko, O, Stanislavchuk, M, Tseluyko, V, Kushnir, M, Asanov, E, Sirenko, Y, Yagensky, A, Collier, D, Gupta, P, Webb, D, Macleod, M, Mclay, J, Peace, A, Arora, S, Buchanan, P, Harris, R, Degarmo, R, Guillen, M, Karns, A, Neutel, J, Paliwal, Y, Pettis, K, Toth, P, Wayne, J, Butcher, B, Diller, P, Oparil, S, Calhoun, D, Brautigam, D, Goldman, J, Rashidi, A, Aslam, N, Haley, W, Andrawis, N, Lang, B, Miller, R, Powell, J, Dewhurst, R, Pritchard, J, Khanna, D, Tang, D, Gabra, N, Jones, C, Scott, C, Luna, B, Mussaji, M, Bhagwat, R, Bauer, M, Mcginty, J, Nambiar, R, Sangrigoli, R, Ross Davis, W, Eaves, W, Mcgrew, F, Awad, A, Bolster, E, Scott, D, Kalirao, P, Dabel, P, Calhoun, W, Gouge, S, Warren, M, Lawrence, M, Jamal, A, El-Shahawy, M, Mercado, C, Kumar, J, Velasquez-Mieyer, P, Busch, R, Lewis, T, Rich, L, Schlaich, Markus P, Bellet, Marc, Weber, Michael A, Danaietash, Parisa, Bakris, George L, Flack, John M, Dreier, Roland F, Sassi-Sayadi, Mouna, Haskell, Lloyd P, Narkiewicz, Krzysztof, Wang, Ji-Guang, Reid, Christopher, Schlaich, Markus, Katz, Ivor, Ajani, Andrew, Biswas, Sinjini, Esler, Murray, Elder, Grahame, Roger, Simon, Colquhoun, David, Mooney, John, De Backer, Tine, Persu, Alexandre, Chaumont, Martin, Krzesinski, Jean-Marie, Vanabsche, Thomas, Girard, Ginette, Pliamm, Lew, Schiffrin, Ernesto, Merali, Fatima, Dresser, George, Vallee, Michel, Jolly, Shivinder, Chow, Stephen, Wang, Jiguang, Mu, Jianjun, Yu, Jing, Yuan, Hong, Feng, Yingqing, Zhang, Xin, Xie, Jianhong, Lin, Ling, Soucek, Miroslav, Widimsky, Jiri, Cifkova, Renata, Vaclavik, Jan, Ullrych, Martin, Lukac, Martin, Rychlik, Ivan, Guldager Lauridsen, Thomas, Kantola, Ilkka, Taurio, Jyrki, Ukkola, Olavi, Ormezzano, Olivier, Gosse, Philippe, Azizi, Michel, Courand, Pierre-Yves, Delsart, Pascal, Tartiere, Jean Michel, Mahfoud, Felix, Schmieder, Roland, Stegbauer, Johannes, Lurz, Philipp, Koziolek, Michael, Ott, Christian, Toursarkissian, Nicole, Tsioufis, Konstantinos, Kyfnidis, Konstantinos, Manolis, Athanasios, Patsilinakos, Sotirios, Zebekakis, Pantelis, Karavidas, Apostolos, Denes, Pall, Bezzegh, Katalin, Zsom, Marianna, Kovacs, Laszlo, Sharabi, Yehonatan, Elias, Mazen, Sukholutsky, Ivetta, Yosefy, Chaim, Kenis, Irina, Atar, Shaul, Volpe, Massimo, Lorenza, Muiesan Maria, Taddei, Stefano, Grassi, Guido, Veglio, Franco, Son, Jung Woo, Kim, Jang-Young, Park, Joong-Il, Lee, Chang Hoon, Lee, Hae-Young, Raugaliene, Rasa, Marcinkeviciene, Jolanta Elena, Kavaliauskiene, Roma, Deinum, Jaap, Kroon, Abraham, van den Born, Bert-Jan, Januszewicz, Andrzej, Tykarski, Andrzej, Walczewska, Jolanta, Gaciong, Zbigniew, Wiecek, Andrzej, Chrostowska, Marzena, Kleinrok, Andrzej, Krekora, Jan, Kania, Grzegorz, Podrazka-Szczepaniak, Anna, Golawski, Cezary, Podziewski, Maciej, Kaczmarek, Barbara, Skoczylas, Grzegorz, Wilkolaski, Andrzej, Wozniak, Iwona, Janik-Palazzolo, Marzena, Rewerska, Barbara, Konradi, Alexandra, Shvarts, Yuriy, Pecherina, Tamara, Nikolaev, Konstantin, Liudmila, Gapon, Orlikova, Olga, Mordovin, Viktor, Petrochenkova, Natalia, Kamalov, Gadel, Kosmacheva, Elena, Tyrenko, Vadim, Gorbunov, Vladimir, Obrezan, Andrey, Supryadkina, Tatiana, Ler, Irina, Kotenko, Oleg, Kuzin, Anatoly, Martinez, Fernando, Redon, Josep, Oliveras, Anna, Beltran Romero, Luis, Shatylo, Valerii, Rudenko, Leonid, Bazylevych, Andriiy, Rudyk, Yurii, Karpenko, Oleksandr, Stanislavchuk, Mykola, Tseluyko, Vira, Kushnir, Mykola, Asanov, Ervin, Sirenko, Yuriy, Yagensky, Andriy, Collier, David, Gupta, Pankaj, Webb, David, MacLeod, Mary, McLay, James, Peace, Aaron, Arora, Samir, Buchanan, Patricia, Harris, Robert, Degarmo, Ronald, Guillen, Mario, Karns, Adam, Neutel, Joel, Paliwal, Yogesh, Pettis, Karlton, Toth, Phillip D., Wayne, Jeffrey M., Butcher, Bain, Diller, Phillip M., Oparil, Suzanne, Calhoun, David, Brautigam, Donald, Flack, John, Goldman, Jesse M., Rashidi, Arash, Aslam, Nabeel, Haley, William, Andrawis, Nabil, Lang, Brian, Miller, Randy, Powell, James, Dewhurst, Robert, Pritchard, James, Khanna, Dinesh, Tang, Dennis, Gabra, Nashwa, Park, Jean, Jones, Conigliaro, Scott, Cranford, Luna, Blanca, Mussaji, Murtaza, Bhagwat, Ravi, Bauer, Michael, McGinty, John, Nambiar, Rajesh, Sangrigoli, Renee, Ross Davis, William, Eaves, William, McGrew, Frank, Awad, Ahmed, Bolster, Eric, Scott, David, Kalirao, Paramjit, Dabel, Pascal, Calhoun, Wesley, Gouge, Steven, Warren, Mark, Lawrence, Mary Katherine, Jamal, Aamir, El-Shahawy, Mohamed, Mercado, Carlos, Kumar, Jayant, Velasquez-Mieyer, Pedro, Busch, Robert, Lewis, Todd, and Rich, Lisa

Abstract

Background: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. Methods: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. Findings: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square m

Published
2022

6. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Author

Schlaich, Markus P, Bellet, Marc, Weber, Michael A, Danaietash, Parisa, Bakris, George L, Flack, John M, Dreier, Roland F, Sassi-Sayadi, Mouna, Haskell, Lloyd P, Narkiewicz, Krzysztof, Wang, Ji-Guang, Reid, Christopher, Schlaich, Markus, Katz, Ivor, Ajani, Andrew, Biswas, Sinjini, Esler, Murray, Elder, Grahame, Roger, Simon, Colquhoun, David, Mooney, John, De Backer, Tine, Persu, Alexandre, Chaumont, Martin, Krzesinski, Jean-Marie, Vanabsche, Thomas, Girard, Ginette, Pliamm, Lew, Schiffrin, Ernesto, Merali, Fatima, Dresser, George, Vallee, Michel, Jolly, Shivinder, Chow, Stephen, Wang, Jiguang, Mu, Jianjun, Yu, Jing, Yuan, Hong, Feng, Yingqing, Zhang, Xin, Xie, Jianhong, Lin, Ling, Soucek, Miroslav, Widimsky, Jiri, Cifkova, Renata, Vaclavik, Jan, Ullrych, Martin, Lukac, Martin, Rychlik, Ivan, Guldager Lauridsen, Thomas, Kantola, Ilkka, Taurio, Jyrki, Ukkola, Olavi, Ormezzano, Olivier, Gosse, Philippe, Azizi, Michel, Courand, Pierre-Yves, Delsart, Pascal, Tartiere, Jean Michel, Mahfoud, Felix, Schmieder, Roland, Stegbauer, Johannes, Lurz, Philipp, Koziolek, Michael, Ott, Christian, Toursarkissian, Nicole, Tsioufis, Konstantinos, Kyfnidis, Konstantinos, Manolis, Athanasios, Patsilinakos, Sotirios, Zebekakis, Pantelis, Karavidas, Apostolos, Denes, Pall, Bezzegh, Katalin, Zsom, Marianna, Kovacs, Laszlo, Sharabi, Yehonatan, Elias, Mazen, Sukholutsky, Ivetta, Yosefy, Chaim, Kenis, Irina, Atar, Shaul, Volpe, Massimo, Lorenza, Muiesan Maria, Taddei, Stefano, Grassi, Guido, Veglio, Franco, Son, Jung Woo, Kim, Jang-Young, Park, Joong-Il, Lee, Chang Hoon, Lee, Hae-Young, Raugaliene, Rasa, Marcinkeviciene, Jolanta Elena, Kavaliauskiene, Roma, Deinum, Jaap, Kroon, Abraham, van den Born, Bert-Jan, Januszewicz, Andrzej, Tykarski, Andrzej, Walczewska, Jolanta, Gaciong, Zbigniew, Wiecek, Andrzej, Chrostowska, Marzena, Kleinrok, Andrzej, Krekora, Jan, Kania, Grzegorz, Podrazka-Szczepaniak, Anna, Golawski, Cezary, Podziewski, Maciej, Kaczmarek, Barbara, Skoczylas, Grzegorz, Wilkolaski, Andrzej, Wozniak, Iwona, Janik-Palazzolo, Marzena, Rewerska, Barbara, Konradi, Alexandra, Shvarts, Yuriy, Pecherina, Tamara, Nikolaev, Konstantin, Liudmila, Gapon, Orlikova, Olga, Mordovin, Viktor, Petrochenkova, Natalia, Kamalov, Gadel, Kosmacheva, Elena, Nikolaev, Konstantin, Tyrenko, Vadim, Gorbunov, Vladimir, Obrezan, Andrey, Supryadkina, Tatiana, Ler, Irina, Kotenko, Oleg, Kuzin, Anatoly, Martinez, Fernando, Redon, Josep, Oliveras, Anna, Beltran Romero, Luis, Shatylo, Valerii, Rudenko, Leonid, Bazylevych, Andriiy, Rudyk, Yurii, Karpenko, Oleksandr, Stanislavchuk, Mykola, Tseluyko, Vira, Kushnir, Mykola, Asanov, Ervin, Sirenko, Yuriy, Yagensky, Andriy, Collier, David, Gupta, Pankaj, Webb, David, MacLeod, Mary, McLay, James, Peace, Aaron, Arora, Samir, Buchanan, Patricia, Harris, Robert, Degarmo, Ronald, Guillen, Mario, Karns, Adam, Neutel, Joel, Paliwal, Yogesh, Pettis, Karlton, Toth, Phillip D., Wayne, Jeffrey M., Butcher, Bain, Diller, Phillip M., Oparil, Suzanne, Calhoun, David, Brautigam, Donald, Flack, John, Goldman, Jesse M., Rashidi, Arash, Aslam, Nabeel, Haley, William, Andrawis, Nabil, Lang, Brian, Miller, Randy, Powell, James, Dewhurst, Robert, Pritchard, James, Khanna, Dinesh, Tang, Dennis, Gabra, Nashwa, Park, Jean, Jones, Conigliaro, Scott, Cranford, Luna, Blanca, Mussaji, Murtaza, Bhagwat, Ravi, Bauer, Michael, McGinty, John, Nambiar, Rajesh, Sangrigoli, Renee, Ross Davis, William, Eaves, William, McGrew, Frank, Awad, Ahmed, Bolster, Eric, Scott, David, Kalirao, Paramjit, Dabel, Pascal, Calhoun, Wesley, Gouge, Steven, Warren, Mark, Lawrence, Mary Katherine, Jamal, Aamir, El-Shahawy, Mohamed, Mercado, Carlos, Kumar, Jayant, Velasquez-Mieyer, Pedro, Busch, Robert, Lewis, Todd, and Rich, Lisa

Abstract

Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension.

Published
2022
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10. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension.

Author

Verweij, Pierre, Danaietash, Parisa, Flamion, Bruno, Ménard, Joël, and Bellet, Marc

Abstract

This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90-109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, P≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%-40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603809. [ABSTRACT FROM AUTHOR]

Published
2020
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11. Effect of the urotensin receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy.

Author

Vogt, Liffert, Chiurchiu, Carlos, Chadha-Boreham, Harbajan, Danaietash, Parisa, Dingemanse, Jasper, Hadjadj, Samy, Krum, Henry, Navis, Gerjan, Neuhart, Eric, Parvanova, Aneliya I., Ruggenenti, Piero, Woittiez, Arend Jan, Zimlichman, Reuven, Remuzzi, Giuseppe, Zeeuw, Dick de, de Zeeuw, Dick, and PROLONG (PROteinuria Lowering with urOteNsin receptor antaGonists) Study Group

Abstract

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population. [ABSTRACT FROM AUTHOR]

Published
2010
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12. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Author

Markus P Schlaich, Marc Bellet, Michael A Weber, Parisa Danaietash, George L Bakris, John M Flack, Roland F Dreier, Mouna Sassi-Sayadi, Lloyd P Haskell, Krzysztof Narkiewicz, Ji-Guang Wang, Christopher Reid, Markus Schlaich, Ivor Katz, Andrew Ajani, Sinjini Biswas, Murray Esler, Grahame Elder, Simon Roger, David Colquhoun, John Mooney, Tine De Backer, Alexandre Persu, Martin Chaumont, Jean-Marie Krzesinski, Thomas Vanassche, Ginette Girard, Lew Pliamm, Ernesto Schiffrin, Fatima Merali, George Dresser, Michel Vallee, Shivinder Jolly, Stephen Chow, Jiguang Wang, Jianjun Mu, Jing Yu, Hong Yuan, Yingqing Feng, Xin Zhang, Jianhong Xie, Ling Lin, Miroslav Soucek, Jiri Widimsky, Renata Cifkova, Jan Vaclavik, Martin Ullrych, Martin Lukac, Ivan Rychlik, Thomas Guldager Lauridsen, Ilkka Kantola, Jyrki Taurio, Olavi Ukkola, Olivier Ormezzano, Philippe Gosse, Michel Azizi, Pierre-Yves Courand, Pascal Delsart, Jean Michel Tartiere, Felix Mahfoud, Roland Schmieder, Johannes Stegbauer, Philipp Lurz, Michael Koziolek, Christian Ott, Nicole Toursarkissian, Konstantinos Tsioufis, Konstantinos Kyfnidis, Athanasios Manolis, Sotirios Patsilinakos, Pantelis Zebekakis, Apostolos Karavidas, Pall Denes, Katalin Bezzegh, Marianna Zsom, Laszlo Kovacs, Yehonatan Sharabi, Mazen Elias, Ivetta Sukholutsky, Chaim Yosefy, Irina Kenis, Shaul Atar, Massimo Volpe, Muiesan Maria Lorenza, Stefano Taddei, Guido Grassi, Franco Veglio, Jung Woo Son, Jang-Young Kim, Joong-Il Park, Chang Hoon Lee, Hae-Young Lee, Rasa Raugaliene, Jolanta Elena Marcinkeviciene, Roma Kavaliauskiene, Jaap Deinum, Abraham Kroon, Bert-Jan van den Born, Andrzej Januszewicz, Andrzej Tykarski, Jolanta Walczewska, Zbigniew Gaciong, Andrzej Wiecek, Marzena Chrostowska, Andrzej Kleinrok, Jan Krekora, Grzegorz Kania, Anna Podrazka-Szczepaniak, Cezary Golawski, Maciej Podziewski, Barbara Kaczmarek, Grzegorz Skoczylas, Andrzej Wilkolaski, Iwona Wozniak, Marzena Janik-Palazzolo, Barbara Rewerska, Aleksandra Konradi, Yuriy Shvarts, Tamara Pecherina, Konstantin Nikolaev, Gapon Liudmila, Olga Orlikova, Viktor Mordovin, Natalia Petrochenkova, Gadel Kamalov, Elena Kosmacheva, Vadim Tyrenko, Vladimir Gorbunov, Andrey Obrezan, Tatiana Supryadkina, Irina Ler, Oleg Kotenko, Anatoly Kuzin, Fernando Martínez García, Josep Redon, Anna Oliveras, Luis Beltran Romero, Valerii Shatylo, Leonid Rudenko, Andriy Bazylevych, Yurii Rudyk, Oleksandr Karpenko, Mykola Stanislavchuk, Vira Tseluyko, Mykola Kushnir, Ervin Asanov, Yuriy Sirenko, Andriy Yagensky, David Collier, Pankaj Gupta, David Webb, Mary MacLeod, James McLay, Aaron Peace, Samir Arora, Patricia Buchanan, Robert Harris, Ronald Degarmo, Mario Guillen, Adam Karns, Joel Neutel, Yogesh Paliwal, Karlton Pettis, Phillip D. Toth, Jeffrey M. Wayne, Michael Bain Butcher, Phillip M. Diller, Suzanne Oparil, David Calhoun, Donald Brautigam, John Flack, Jesse M. Goldman, Arash Rashidi, Nabeel Aslam, William Haley, Nabil Andrawis, Brian Lang, Randy Miller, James Powell, Robert Dewhurst, James Pritchard, Dinesh Khanna, Dennis Tang, Nashwa Gabra, Jean Park, Conigliaro Jones, Cranford Scott, Blanca Luna, Murtaza Mussaji, Ravi Bhagwat, Michael Bauer, John McGinty, Rajesh Nambiar, Renee Sangrigoli, William Ross Davis, William Eaves, Frank McGrew, Ahmed Awad, Eric Bolster, David Scott, Paramjit Kalirao, Pascal Dabel, Wesley Calhoun, Steven Gouge, Mark Warren, Mary Katherine Lawrence, Aamir Jamal, Mohamed El-Shahawy, Carlos Mercado, Jayant Kumar, Pedro Velasquez-Mieyer, Robert Busch, Todd Lewis, Lisa Rich, Public and occupational health, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, APH - Personalized Medicine, ACS - Heart failure & arrhythmias, Schlaich, M, Bellet, M, Weber, M, Danaietash, P, Bakris, G, Flack, J, Dreier, R, Sassi-Sayadi, M, Haskell, L, Narkiewicz, K, Wang, J, Reid, C, Katz, I, Ajani, A, Biswas, S, Esler, M, Elder, G, Roger, S, Colquhoun, D, Mooney, J, De Backer, T, Persu, A, Chaumont, M, Krzesinski, J, Vanabsche, T, Girard, G, Pliamm, L, Schiffrin, E, Merali, F, Dresser, G, Vallee, M, Jolly, S, Chow, S, Mu, J, Yu, J, Yuan, H, Feng, Y, Zhang, X, Xie, J, Lin, L, Soucek, M, Widimsky, J, Cifkova, R, Vaclavik, J, Ullrych, M, Lukac, M, Rychlik, I, Guldager Lauridsen, T, Kantola, I, Taurio, J, Ukkola, O, Ormezzano, O, Gosse, P, Azizi, M, Courand, P, Delsart, P, Tartiere, J, Mahfoud, F, Schmieder, R, Stegbauer, J, Lurz, P, Koziolek, M, Ott, C, Toursarkissian, N, Tsioufis, K, Kyfnidis, K, Manolis, A, Patsilinakos, S, Zebekakis, P, Karavidas, A, Denes, P, Bezzegh, K, Zsom, M, Kovacs, L, Sharabi, Y, Elias, M, Sukholutsky, I, Yosefy, C, Kenis, I, Atar, S, Volpe, M, Lorenza, M, Taddei, S, Grassi, G, Veglio, F, Son, J, Kim, J, Park, J, Lee, C, Lee, H, Raugaliene, R, Marcinkeviciene, J, Kavaliauskiene, R, Deinum, J, Kroon, A, van den Born, B, Januszewicz, A, Tykarski, A, Walczewska, J, Gaciong, Z, Wiecek, A, Chrostowska, M, Kleinrok, A, Krekora, J, Kania, G, Podrazka-Szczepaniak, A, Golawski, C, Podziewski, M, Kaczmarek, B, Skoczylas, G, Wilkolaski, A, Wozniak, I, Janik-Palazzolo, M, Rewerska, B, Konradi, A, Shvarts, Y, Pecherina, T, Nikolaev, K, Liudmila, G, Orlikova, O, Mordovin, V, Petrochenkova, N, Kamalov, G, Kosmacheva, E, Tyrenko, V, Gorbunov, V, Obrezan, A, Supryadkina, T, Ler, I, Kotenko, O, Kuzin, A, Martinez, F, Redon, J, Oliveras, A, Beltran Romero, L, Shatylo, V, Rudenko, L, Bazylevych, A, Rudyk, Y, Karpenko, O, Stanislavchuk, M, Tseluyko, V, Kushnir, M, Asanov, E, Sirenko, Y, Yagensky, A, Collier, D, Gupta, P, Webb, D, Macleod, M, Mclay, J, Peace, A, Arora, S, Buchanan, P, Harris, R, Degarmo, R, Guillen, M, Karns, A, Neutel, J, Paliwal, Y, Pettis, K, Toth, P, Wayne, J, Butcher, B, Diller, P, Oparil, S, Calhoun, D, Brautigam, D, Goldman, J, Rashidi, A, Aslam, N, Haley, W, Andrawis, N, Lang, B, Miller, R, Powell, J, Dewhurst, R, Pritchard, J, Khanna, D, Tang, D, Gabra, N, Jones, C, Scott, C, Luna, B, Mussaji, M, Bhagwat, R, Bauer, M, Mcginty, J, Nambiar, R, Sangrigoli, R, Ross Davis, W, Eaves, W, Mcgrew, F, Awad, A, Bolster, E, Scott, D, Kalirao, P, Dabel, P, Calhoun, W, Gouge, S, Warren, M, Lawrence, M, Jamal, A, El-Shahawy, M, Mercado, C, Kumar, J, Velasquez-Mieyer, P, Busch, R, Lewis, T, and Rich, L

Subjects
Endothelin Receptor Antagonists, Treatment Outcome, Double-Blind Method, Hypertension, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Humans, General Medicine, Blood Pressure Monitoring, Ambulatory, resistant hypertension, Dual endothelin antagonist aprocitentan, Antihypertensive Agents
Abstract

Contains fulltext : 286841.pdf (Publisher’s version ) (Closed access) BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p

Published
2022

13. Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan.

Author

Danaietash P, Verweij P, Wang JG, Dresser G, Kantola I, Lawrence MK, Narkiewicz K, Schlaich M, and Bellet M

Subjects
Antihypertensive Agents, Blood Pressure, Double-Blind Method, Humans, Pyrimidines, Single-Blind Method, Sulfonamides adverse effects, Hypertension chemically induced, Hypertension diagnosis, Hypertension drug therapy
Abstract

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel-group Phase 3 study and its three-part design assesses the short-term and sustained long-term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. The 4-week placebo run-in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4-week double-blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32-week single-blind part with aprocitentan 25 mg; and (3) a 12-week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Published
2022
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14. Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies.

Author

Ratner P, Andrews CP, Hampel FC, Martin B, Mohar DE, Bourrelly D, Danaietash P, Mangialaio S, Dingemanse J, Hmissi A, and van Bavel J

Abstract

Background: Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks., Methods: A Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100-1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS)., Results: 579 participants were randomized in the Phase 2 trial (mean age 41.6-43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5-40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (-0.15 [95% CI -0.29, -0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (-0.02 [95% CI -0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile., Conclusions: The Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies. Trial registration NCT01241214 and NCT01484119.

Published
2017
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